Matrifibrocytes Redefine Cardiac Fibrosis: From Terminal Differentiation to Translational Modulation

Figures

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  FIGURE 1. Temporal dynamics of fibroblast states after myocardial infarction. After myocardial injury, quiescent CFs (Tcf21 +, Pdgfra +, Ddr2 +, and Dcn+) rapidly activate into α‐smooth muscle actin–positive (Acta2 +) MFs that produce ECM to stabilize the injured myocardium. MFs dominate during the early reparative phase (day 3–7 post‐MI) but progressively decline by day 14 as the wound matures. A subset of fibroblast‐lineage cells subsequently transitions into a terminal, non‐contractile state known as the MFC, characterized by the loss of stress fibres and upregulation of cartilage‐like ECM genes (Comp, Chad, Thbs4, and Sfrp2). The lower panel illustrates the relative temporal abundance of each cell population. Quiescent CFs rapidly decrease after injury (blue), MFs peak during early scar formation and resolve by day 14 (orange), while MFCs emerge around day 10 and persist as the dominant fibroblast population in the mature scar (day 14–28) (grey).

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  FIGURE 2. Molecular and transcriptional regulation of Matrifibrocyte differentiation. CFs transition from a quiescent, low‐tension state to activated MFs driven by TGF‐β/SMAD, IL‐11 and YAP/TAZ signalling. Terminal differentiation into MFCs is associated with Smad7 upregulation and TGF‐β suppression, along with proposed regulatory modules, including YAP/TAZ reprogramming, Sfrp2–Wnt modulation, Comp–Notch3 signalling and Thbs4–Atf6α–mediated ER stress adaptation, which collectively stabilize the ECM and maintain scar homeostasis.

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  FIGURE 3. Functional roles of MFCs in the mature scar microenvironment. Matrifibrocytes deploy coordinated programs for extracellular‐matrix stabilization and cross‐linking (Comp, Chad, Thbs4, Dpt), ER and metabolic adaptation via Thbs4–Atf6α, anti‐inflammatory signalling (Sfrp2, Wisp2, Smad7), and paracrine or intercellular feedback including Comp–Notch3 and ECM–integrin coupling. Together these modules establish a quiescent, stress‐adapted scar niche that preserves ECM integrity and limits adverse remodelling.

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  FIGURE 4. Therapeutic and research framework centered on the matrifibrocyte state. The MFC is a pharmacologically and transcriptionally modifiable fibroblast state linking scar stabilization and regeneration. Left: Pharmacologic activation (e.g., MCB‐613, salinomycin) enhances MFC maturation, stabilizes ECM, and reduces inflammation. Right: Reprogramming strategies (e.g., MGTH factors) reverse terminal differentiation and promote cardiomyocyte regeneration. Bottom: Outstanding questions concern upstream regulation, reversibility, and precise targeting of MFCs to balance repair and recovery.